Of podophyllotoxin

Podophyllotoxin, a plant lignan, is a potent antimitotic agent (Figure 6.61). An enantioselective synthesis of (—)-podophyllotoxin was achieved via the enzymatic desymmetrization of an advanced meso-diacetate, through PPL-mediated diester hydrolysis [157]. 

The GASPE spectrum of podophyllotoxin is shown. The signals at 8 56.0,108.6, and 152.0 each represent two carbons in identical magnetic environments, while the signal at 8 147.6 also represents two carbons that accidentally appear at the same chemical shift. Assign chemical shift values to various protonated and quaternary carbons in the structure. 

The basic INEPT spectrum cannot be recorded with broad-band proton decoupling, since the components of multiplets have antiphase disposition. With an appropriate increase in delay time, the antiphase components of the multiplets appear in phase. In the refocussed INEPT experiment, a suitable refocusing delay is therefore introduced that allows the C spin multiplet components to get back into phase. The pulse sequences and the resulting spectra of podophyllotoxin (Problem 2.21) from the two experiments are given below ... 

The COSY-45 spectrum of podophyllotoxin and its H-NMR data are shown. Assign and interpret the H/ H cross-peaks in the COSY spectrum. 

The HOHAHA spectrum (100 ms) of podophyllotoxin is presented. The HOHAHA, or TOCSY (total correlation spectroscopy), spectrum (100 ms) shows coupling interactions of all protons within a spin network, irrespective of whether they are directly coupled to one another or not. As in COSY spectra, peaks on the diagonal are ignored as they arise due to magnetization that is not modulated by coupling interactions. Podophyllotoxin has only one large spin system, extending from the C-1 proton to the C4 and 015 protons. Identify all homonuclear correlations of protons within this spin system based on the crosspeaks in the spectrum. 

The HMBC spectrum of podophyllotoxin is shown. The cross-peaks in the HMBC spectrum represent long-range heteronuclear H/ C interactions within the same substructure or between different substructures. Interpretation should start with a readily assignable carbon (or proton), and then you identify the proton/s (or carbon/s) with which it has coupling interactions. Then proceed from these protons, and look for the carbon two, three, or, occasionally, four bonds away. One-bond heteronuclear interactions may also appear in HMBC spectrum. 

Twelve cross-peaks (A-L) are visible in the HETCOR spectrum of podophyllotoxin, representing 13 protonated carbons in the molecule. 

The HMQC spectrum of podophyllotoxin shows heteronuclear crosspeaks for all 13 protonated carbons. Each cross-peak represents a one-bond correlation between the C nucleus and the attached proton. It also allows us to identify the pairs of geminally coupled protons, since both protons display cross-peaks with the same carbon. For instance, peaks A and B represent the one-bond correlations between protons at 8 4.10 and 4.50 with the carbon at 8 71.0 and thus represent a methylene group (C-15). Cross-peak D is due to the heteronuclear correlation between the C-4 proton at 8 4.70 and the carbon at 8 72.0, assignable to the oxygen-bearing benzylic C-4. Heteronuclear shift correlations between the aromatic protons and carbons are easily distinguishable as cross-peaks J-L, while I represents C/H interactions between the methylenedioxy protons (8 5.90) and the carbon at 8 101.5. The C-NMR and H-NMR chemical shift assignments based on the HMQC cross-peaks are summarized on the structure. 

The ROESY spectrum of podophyllotoxin exhibits a number of crosspeaks (A-D) representing interactions between dipolarly coupled (space coupling) hydrogens, which can be helpful to determine the stereochemistry at different asymmetric centers. For example, based on the assumption that the C-1 proton (8 4.53) is /3-oriented, we can trace out the stereochemistry of other asymmetric centers. Cross-peak B represents dipolar coupling between the C-1 proton (8 4.53) and the C-2 proton (8 2.8), thereby confirming that the C-2 proton is also... 

Etoposide (XV) is a semisynthetic gylcoside derivative of podophyllotoxin, which is one of the most extensively used anticancer drugs in the treatment of various types of tumors [64,65]. The anticancer activity of this drug is mainly due to its ability to inhibit an ubiquitous and essential enzyme human DNA topo II [66,67]. Despite its extensive use in the treatment of cancers, it has several limitations, such as poor water solubility, drug resistance, metabolic inactivation, myelosuppression, and toxicity [68]. In order to overcome these... 

Scheme 2.117. Three-component domino reaction leading to aza-analogs of podophyllotoxin (2-508).

Scheme 3.16. Domino radical cyclization in the total synthesis of (+)-podophyllotoxin (3-59).

Scheme 5.19. Photoenolization/Diels-Alder reaction sequence is the synthesis of podophyllotoxin (5-103).

When the TMS group is absent and if the reaction is carried out in methanol, a platinum(ll)-catalyzed alkoxycy-clization takes place (Scheme 87).308 This cyclization catalyzed by Pt(ll) was found to be mechanistically similar to the carbohydroxypalladation reported by Genet.309 310 This process has intrinsic importance in organic synthesis since it allows the simultaneous and generally stereoselective formation of a C-O and a C-C bond to occur from an enyne system. This reaction has been applied for the synthesis of a key intermediate of podophyllotoxin.311... 

Two derivatives of podophyllotoxin (38), etoposide (39) and tenipo-side (40), are further examples of the use of a natural product as a drug lead. In 1890, podophyllotoxin was isolated from Podophyllumpeltatum L. (American May Apple), and in 1948, it was shown to have antineoplastic activity in mice bearing tumors. Then, hundreds of podophyllotoxin... 

The plant. Podophyllum hexandrum (Podophyllaceae Berberidaceae), produces podophyllotoxin (3) and its glycoside, both of which are effective anticancer agents. Commercial production of podophyllotoxin from... 

Podophyllotoxin (3) is a precursor to the three cUnically used anticancer drugs, etoposide (4), teniposide (5), and etoposide phosphate (6). Its mechanism of action involves inhibition of tubuUn polymerization and disruption of mitosis during metaphase of the cell cycle. Both etoposide and teniposide are modifications of podophyllotoxin specifically designed to increase the water solubility, reduce gastric toxicity in addition to inhibiting topoisomerase II, and disrupting the cell cycle. 

Puri SC The endophytic fungus Trametes hirsuta zs z novel ahemzxive source of podophyllotoxin and related aryl tetrahn li zirs, J Biotechnol 122 494—510, 2006. 

Partially hydrogenated quinoline cores are also present in some important bioactive compounds. For example, the 4-aza-analogs of Podophyllotoxin, a plant lignan that inhibits microtubule assembly, revealed to be more potent and less toxic anticancer agents. In 2006, Ji s group reported a green multicomponent approach to a new series of these derivatives, consisting of the reaction of either tetronic acid or 1,3-indanedione with various aldehydes and substituted anilines in water under microwave irradiation conditions (Scheme 26) [107]. For this efficient and eco-friendly transformation, the authors proposed a mechanism quite similar to the one that was postulated for the synthesis of tetrahydroquinolines in the precedent section. 

Etoposide (VePesid) is a semisynthetic derivative of podophyllotoxin that is produced in the roots of the American mandrake, or May apple. Unlike podophyllotoxin and vinca alkaloids, etoposide does not bind to microtubules. It forms a complex with the enzyme topoiso-merase II, which results in a single-strand breakage of DNA. It is most lethal to cells in the S- and Gj-phases of the cell cycle. Drug resistance to etoposide is thought to be caused by decreased cellular drug accumulation. 

Podophyllum resin, an alcoholic extract of Podophyllum peltatum, commonly known as mandrake root or May apple, is used in the treatment of condyloma acuminatum and other verrucae. It is a mixture of podophyllotoxin, and peltatin, desoxypodophyllotoxin, dehydropodophyllotoxin, and other compounds. It is soluble in alcohol, ether, chloroform, and compound tincture of benzoin. 

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